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Artesunate Inhibits the Proliferation and Migration of Cutaneous Squamous Cell Carcinoma by Regulating the
Xinyan Huang1, Wenxi Wang2, Songzhao Zhang3
1Dermatology Department, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou 310009, China.
Abstract:
The incidence of cutaneous squamous cell carcinoma (CSCC) is increasing rapidly. This study discussed the effects of artesunate (ART) on CSCC cell proliferation and migration via the solute carrier family 7 member 11 (SLC7A11)-glutathione peroxidase 4 (GPX4) pathway. MTT assessed cell viability and analyzed the IC50 value (69.26 μM). Accordingly, human CSCC cells (A431) were cultured in vitro, and treated with 70 μM ART, Ferrostatin-1, oe-SLC7A11, and C646, with cell biological behavior assessed. The potential targets of ART were predicted. p53 acetylation and protein stability and ART-p300 binding were examined. Thymusless nude mice were subcutaneously inoculated with A431 cells, and treated with ART and C646. ART-treated A431 cells showed weakened proliferation, migration, lactate dehydrogenase levels, oxidized glutathione/glutathione ratio, reactive oxygen species, malondialdehyde, and active Fe2+ levels, which could be reversed by suppressing ferroptosis. ART promoted p53 acetylation and protein stability and curbed the SLC7A11-GPX4 pathway by targeting p300. ART stimulated ferroptosis via the SLC7A11-GPX4 pathway, thereby repressing CSCC cell proliferation and migration, which were counteracted by p300 inhibition. ART regulated the SLC7A11-GPX4 pathway by up-regulating the p300-p53 axis, thereby hindering tumor growth in vivo. Collectively, ART inhibits CSCC proliferation and migration by modulating the SLC7A11-GPX4 pathway through the p300-p53 axis.
Insights
Artesunate (ART) inhibits cutaneous squamous cell carcinoma (CSCC) growth by targeting the p300-p53 axis, which modulates the solute carrier family 7 member 11 (SLC7A11)-glutathione peroxidase 4 (GPX4) pathway and induces ferroptosis.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Cutaneous squamous cell carcinoma (CSCC) incidence is rising globally.
- Understanding novel therapeutic targets for CSCC is crucial.
Purpose of the Study:
- To investigate the effects of artesunate (ART) on CSCC proliferation and migration.
- To elucidate the underlying molecular mechanisms involving the SLC7A11-GPX4 pathway and the p300-p53 axis.
Main Methods:
- In vitro studies using human CSCC (A431) cells treated with ART, Ferrostatin-1, oe-SLC7A11, and C646.
- Assessment of cell viability (MTT assay), proliferation, migration, and ferroptosis markers.
- In vivo studies using a mouse xenograft model.
- Analysis of p53 acetylation, protein stability, and ART-p300 binding.
Main Results:
- ART significantly inhibited CSCC cell proliferation and migration.
- ART induced ferroptosis by suppressing the SLC7A11-GPX4 pathway.
- ART promoted p53 acetylation and protein stability by targeting p300, thereby upregulating the p300-p53 axis.
- ART hindered tumor growth in vivo.
Conclusions:
- Artesunate effectively inhibits CSCC progression by modulating the SLC7A11-GPX4 pathway via the p300-p53 axis.
- ART represents a potential therapeutic agent for CSCC treatment.
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